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A series of omega-dialkylaminoalkyl esters of N-phenyl aminethiocarboximidic acids was prepared by reaction of N-phenyl 1-pyrrolidine, 1-piperidine, 4-morpholine, 1,2,3,4-tetrahydro-1-quinoline, 1,2,3,4-tetrahydro-2-isoquinoline, 10-phenothiazine, N-phenyl-2-pyridylamine and N-benzyl-2-pyridylamine-carbothioamides (prepared in situ from the appropriate secondary amine and phenyl isothiocyanate) with a number of omega-chloroalkyldialkylamines in anhydrous DMF or THF solution in the presence of sodium hydride. Good yields of the above esters were obtained provided that sodium hydride was added initially or after the formation of 3,3-disubstituted 1-phenylthiourea, according to the nature of the secondary amine. Some esters showed in mice local anesthetic activity comparable with that of lidocaine, as well as moderate hypoglycemic, antiarrhythmic, analgesic, antiacetylcholine, H1-antithistamine and platelet antiaggregating activities.

The cardiovascular effects induced by L-glutamic acid (G) on the cardiovascular apparatus of normotensive ethyl urethane-anaesthetized rats have been evaluated. (a) When administered i.v. (1 to 100 mg/kg) G induced a transitory and dose-dependent increase of arterial pressure (AP) with very moderate sinus bradycardia. It was antagonized by L-glutamic acid diethyl ester (GDEE, 0.1 to 100 mg/kg i.v.). (b) The intracerebroventricular (i.c.v.) administration of G (third ventricle, right lateral ventricle, posterior hypothalamus and striatum) at a dose of 0.1 to 10 mg/an induced a transitory and dose-dependent increase of AP, abolished by i.c.v. GDEE (1 to 10 mcg/an). (c) G hypertension was reduced by several procedures, i.e. catecholamine depletion, alpha 1, alpha 1 and alpha 2 or beta adrenergic blocks, alpha 2 central adrenergic stimulation, Ca2+ transmembrane or gangliary block, surrenectomy, and spinal transection at C7. (d) Atropine, bilateral vagotomy and sinus carotidal denervation increased G hypertension. (e) Therefore the bradycardia does seem to be due to a reflex-mediated effect via sinus carotid and aortic baroreceptors. (f) These data show that glutamergic transmission also participates through a central mechanism in the regulation of cardiovascular function in rats, via an increase in central sympathetic efferent activity.

In rats intoxicated with doxorubicin, vasomotor responses were evaluated 12 hr after the last dosage. In rats pretreated with doxorubicin, hypertensive responses to L-norepinephrine and L-epinephrine, and hypertension by occlusion of both common carotid arteries were significantly (p0.05) reduced when compared with controls. Doxorubicin pretreatment also significantly reduced the arterial hypotension due to L-isoprenaline. In rats intoxicated with doxorubicin, pretreatment with L-sulpiride (12.5 to 50 mg/Kg/day for 30 days in drinking water ad libitum) did not modify the effects of doxorubicin on vasomotor reactivity. In contrast, pretreatment with amitriptyline (12.5 to 50 mg/Kg/day in drinking water ad libitum for 30 days) potentiated the inhibitory effects of doxorubicin on vasomotor responses. In conclusion, our research shows that doxorubicin intoxication induces a significant reduction of alpha- and beta-adrenergic reactivity and of baroreceptor activity.

Eventual pharmacological interactions induced by teicoplanin administration associated with oral hypoglycemic (phenformin and glibenclamide) and oral anticoagulant (warfarin) drugs have been experimentally evaluated. The administration of teicoplanin (3-15 mg/kg/die by endoperitoneal route) to the rat for 4 days did not significantly (P greater than 0.05) modify glycemia, prothrombin and partial thromboplastin times, the hypoglycemic effect of phenformin (2.5 mg/kg/die/4 days) or glibenclamide (0.5 mg/kg/die/4 days) nor the anticoagulant effect of warfarin (0.5 mg/kg/die/4 days). In conclusion, our results document that teicoplanin does not interfere with the activity of phenformin, glibenclamide or sodium warfarin.

Experimental research has documented that fenoverine is a depressant drug mostly active on the intestinal smooth muscle; however, it is also active on other tissues as well as on the genito-urinary tract. Fenoverine may be considered a synchronizer of smooth muscle effective in modulating the intracellular influx of calcium into the cell and its release from the intracellular pool. Fenoverine causes a reduction of the excitatory junction potential (EJP) in intestinal smooth muscle by stimulating parasympathetic efferent fibres without any change in the inhibitory junction potential (IJP). This also occurs in the presence of atropine. Fenoverine reduces the intracellular Ca2+ concentration by decreasing the calcium gradient across the cell membrane, as well as decreasing the release of Ca2+ from the intestinal pool more intensely than papaverine (but less intensely than nifedipine, verapamil or diltiazem). This phenomenon has been observed in the intestinal smooth muscle and also in the genito-urinary tract.

Vasomotor reactivity has been evaluated in rats exposed perinatally and postnatally to thallium sulphate (1 mg/dl in their drinking water ad libitum). Prenatal and postnatal exposure to thallium did not modify the values of the systolic arterial blood pressure on the 30th and 60th day in pups of normotensive and DOCA-hypertensive rats. The hypertensive responses induced by endosinusal carotid hypotension and by 1-noradrenaline in pups of normotensive and DOCA-hypertensive rats, exposed or not exposed to thallium sulphate, were more intensive on the 60th than on the 30th day. Similar effects were observed for the hypotensive responses induced by 1-isoprenaline and acetylcholine. Prenatal exposure to thallium did not modify hypertensive responses induced by endosinusal carotid hypotension on the 30th and 60th days, but it caused a decrease of hypertensive responses induced by 1-noradrenaline on the 30th and 60th days and hypotensive responses induced by 1-isoprenaline and acetylcholine exclusively on the 60th day. Postnatal exposure to thallium did not modify hypertensive responses induced by endosinusal carotid hypotension and hypotensive responses induced by acetylcholine, but it caused a decrease of hypertensive responses induced by 1-noradrenaline on the 30th and 60th days in pups of normotensive rats and exclusively on the 60th day in pups of DOCA-hypertensive rats. Moreover, postnatal exposure to thallium caused a decrease of the hypotensive response induced by 1-isoprenaline exclusively on the 60th day. Our findings show that prenatal and postnatal exposure to thallium sulphate modifies the rat's developing vascular autonomic nervous system with a reduction of the α, β-adrenergic and muscarinic vasomotor reactivity.

In conscious rats with normal arterial blood pressure or with spontaneous or DOC induced hypertension, effects of drugs increasing (cycloserine, ethanolamine- o -sulphate, piracetam, chlordesmethyldiazepam) or depressing (bicuculline, Ro 15-1788, PK 11195) GABAergic reactivity were evaluated on the arterial hypotension and sinus bradycardia induced by clonidine. Clonidine was administered orally by gastric gavage (0.1–1 mg/kg). Pretreatment with cycloserine, ethanolamine- o -sulphate, piracetam or chlordesmethyldiazepam increased the hypotension and sinus bradycardia induced by clonidine. On the contrary, pretreatment with bicuculline or Ro 15-1788 reduced the cardiovascular effects of clonidine. These results suggest that the GABAergic system is involved in cardiovascular effects of clonidine in normotensive and hypertensive rats.